Field of the Invention
The present invention relates generally to the fields of autoimmune diseases. More specifically, the present invention relates to uses of ingested (orally administered) tocilizumab in the treatment of autoimmune diseases.
Description of the Related Art
The following abbreviations may be used herein. ACTH—Adrenocorticotropin hormone, α-MSH—alpha-melanocyte stimulating hormone; CR-EAE—chronic relapsing experimental autoimmune encephalomyelitis; DTH—delayed type hypersensitivity; DPBS—Dulbecco's phosphate buffered saline, DMARD—disease modifying anti-rheumatic drugs; GALT—gut associated lymphoid tissue; PP—Peyer's Patch; TCZ—tocilizumab; SIRS—soluble immune response suppressor; SPF—specific pathogen free; SST—somatostatin; TCZ—tocilizumab; and Treg—T regulatory cell.
EAE is a T cell mediated inflammatory autoimmune process of the CNS that resembles in some aspects the human demyelinating disease multiple sclerosis (MS) (1) and provides a useful animal model for the evaluation of potential therapies for cellular mediated autoimmune diseases (2-4). Ingested proteins such as type I IFN (5), SIRS peptide 1-21 (6), α-MSH (7), ACTH (8) and SST (9) inhibit clinical attacks and inflammation in acute EAE (5, 10).
Overproduction of IL-6 has been implicated in the disease pathology of several inflammatory and autoimmune disorders, including rheumatoid arthritis (RA), Castleman's disease, Crohn's disease and systemic-onset juvenile idiopathic arthritis (11). Tocilizumab is a humanized antihuman IL-6 receptor antibody that recognizes both the membrane-bound and the soluble form IL-6R and specifically blocks IL-6 activity (12).
Phase I and II studies of tocilizumab conducted in children with systemic-onset juvenile idiopathic arthritis revealed that tocilizumab reduced the typical symptoms of inflammation attributable to the continuous elevation of IL-6 and sIL-6R levels in serum (13). In a double-blind, randomised, placebo-controlled, parallel group phase III study, 623 patients with moderate to severe active rheumatoid arthritis had significant improvement after rescue therapy with tocilizumab (14). Tocilizumab monotherapy also provided radiographic benefit in patients with rheumatoid arthritis (15).
In January 2010, tocilizumab (RoActemra®; Chugai/Roche), a first-in-class humanized monoclonal antibody that binds specifically to both sIL-6R and mIL-6R and inhibits IL-6R-mediated signaling was approved for patients with moderate to severe rheumatoid arthritis unresponsive to available DMARDs (11-16).
Parenteral tocilizumab can also be effective in other inflammatory diseases including neuromyelitis optica (NMO) by reducing anti-AQP4 autoantibodies (17). Tocilizumab is currently being explored in a large number of autoimmune conditions (18) and is known to have activity in simian arthritis (19) suggesting cross-reactivity in other mammals.
IL-6 transgenic mice developed severe neurologic disease characterized by tremor, ataxia, and seizure (20). IL-6-deficient mice were completely resistant to MOG EAE (21). IL-6 is elevated in the spinal cord and CSF of mice with active EAE but IL-6 administration was therapeutic (22).
Therefore, the prior art is deficient in the use of oral, ingested tocilizumab in the treatment of autoimmune diseases such as multiple sclerosis. The present invention fulfills this long-standing need and desire in the art.